Amplification of depolarization-induced and ryanodine-sensitive cytosolic Ca2+ elevation by synthetic carbocyclic analogs of cyclic ADP-ribose and their antagonistic effects in NG108-15 neuronal cells

金沢大学大学院医学系研究科We synthesized analogs modified in the ribose unit (ribose linked to N1 of adenine) of cyclic ADP-ribose (cADPR), a Ca2+-mobilizing second messenger. The biological activities of these analogs were determined in NG108-15 neuroblastoma × glioma hybrid cells that were pre-loaded with fura-2 acetoxymethylester and subjected to whole-cell patch-clamp. Application of the hydrolysis-resistant cyclic ADP-carbocyclicribose (cADPcR) through patch pipettes potentiated elevation of the cytoplasmic free Ca2+ concentration ([Ca2+]i) at the depolarized membrane potential. The increase in [Ca2+]i evoked upon sustained membrane depolarization was significantly larger in cADPcR-infused cells than in non-infused cells and its degree was equivalent to or significantly greater than that induced by cADPR or β-NAD+. 8-chloro-cADPcR and two inosine congeners (cyclic IDP-carbocyclic-ribose and 8-bromo-cyclic IDP-carbocyclic-ribose) did not induce effects similar to those of cADPcR or cADPR. Instead, 8-chloro-cADPcR together with cADPR or cADPcR caused inhibition of the depolarization-induced [Ca2+]i increase as compared with either cADPR or cADPcR alone. These results demonstrated that our cADPR analogs have agonistic or antagonistic effects on the depolarization-induced [Ca2+]i increase and suggested the presence of functional reciprocal coupling between ryanodine receptors and voltage-activated Ca 2+ channels via cADPR in mammalian neuronal cells. © 2005 International Society for Neurochemistry

Identification of the Occipito-Pontine Tract Using Diffusion-Tensor Fiber Tracking in Adult-Onset Adrenoleukodystrophy with Topographic Disorientation

X-linked adrenoleukodystrophy is a severe and progressive neurodegenerative disease caused by the peroxisomal transporter ATP-binding cassette, subfamily D, member 1 gene mutations. The defect of this gene product results in accumulation of very-long-chain fatty acids in organs and serum, central demyelination, and peripheral axonopathy. Although there are different magnetic resonance (MR) findings which reflect various phenotypes in adrenoleukodystrophy, some cases present with specific symmetrical occipital white-matter lesions. We describe a patient with adult-onset X-linked adrenoleukodystrophy with topographic disorientation, whose brain MR images revealed T2-signal hyperintensity along the occipito-pontine tract and lateral lemnisci, but not in the cortico-spinal tract in the brainstem. The occipito-pontine tract and lateral lemnisci were clearly detected using diffusion-tensor fiber tracking, suggesting that the topographic disorientation of this patient might be related to the occipito-pontine tract. MR tractography can effectively identify the occipito-pontine tract and may help to localize the fibers associated with clinical symptoms

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Resolvin E3 attenuates lipopolysaccharide-induced depression-like behavior in mice

Eicosapentaenoic acid (EPA)-derived resolvin E1 (RvE1) and E2 (RvE2) have antidepressant effects. Here, we investigated the antidepressant effects of resolvin E3 (RvE3) in a mouse model of lipopolysaccharide (LPS)-induced depression. We observed that LPS (0.8 mg/kg, i.p.) significantly increased immobility time on the tail suspension test, and this depression-like behavior was dose-dependently attenuated by intracerebroventricular infusion of RvE3 (10 or 100 ng). No effects of LPS or intracerebroventricular infusion of RvE3 on locomotor activity were observed. These results indicate that RvE3, as well as RvE1 and RvE2, have antidepressant effects. (C) 2018 The Authors. Production and hosting by Elsevier B.V

PK-PD modeling of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine and the enhanced antitumor effect of its phospholipid derivatives in long-circulating liposomes

The efficacy of an antitumor nucleoside, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (3'-ethynylcytidine, ECyd), was analyzed in vitro and in vivo. The in vivo antitumor effect of ECyd encapsulated into long-circulating liposomes was also examined. Based on pharmacokinetic (PK) and pharmacodynamic (PD) analyses, a model that quantitatively explains the in vivo effects of ECyd was proposed, using the concept of minimum effective concentration. The model suggests that ECyd followed a time-dependent mechanism of action in vivo, and that availability of ECyd in tumor tissue was highly important. To improve the availability of ECyd, its phospholipid derivatives were synthesized and encapsulated into long-circulating liposomes, which increased the antitumor effect. These results indicate that it is very important to design carriers of antitumor drugs based on PK-PD modeling